Development of 18F PET radiotracers for M2 microglia as diagnostics for multiplesclerosis pathogenesis

开发用于 M2 小胶质细胞的 18F PET 放射性示踪剂作为多发性硬化症发病机制的诊断

• 批准号: 10440539
• 负责人: Paul Anthony Stupple
• 金额: $ 28.82万
• 依托单位: MONASH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-15 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10440539
• 关键词: ABCG2 gene; Adult; Affect; Affinity; Animal Model; Anti-Inflammatory Agents; Autoradiography; Binding; Binding Sites; Biological Markers; Biological Process; Brain; C57BL/6 Mouse; Caucasians; Cells; Clinical; Clinical Research; Clinical Trials; Cuprizone; Development; Diagnostic; Diagnostic Reagent; Digit structure; Disease; Disease Outcome; Dose; Equipment; Exhibits; FLT3 gene; Failure; Fluorides; Fluorine; Freezing; Future; Genes; Image; Immune; Immunohistochemistry; In Vitro; Inflammatory; Inflammatory Response; Injury; Kinetics; Laboratories; Lead; Lesion; Ligands; Link; MERTK gene; Measures; Mediator of activation protein; Medical Care Costs; Microglia; Modeling; Monitor; Multiple Sclerosis; Multiple Sclerosis Lesions; Mus; Nature; Nerve Degeneration; Nervous system structure; Outcome; Pathogenesis; Pathogenicity; Patients; Penetration; Pharmaceutical Preparations; Phase; Phenotype; Positron-Emission Tomography; Predisposition; Property; Proteins; Radioactive; Radiochemistry; Receptor Protein-Tyrosine Kinases; Rodent; Route; Scanning; Signal Transduction; Slice; Solubility; Stratification; Structure; Techniques; Testing; Therapeutic Intervention; Time; Tissues; Tracer; Translational Research; Variant; Work; blood-brain barrier permeabilization; cytokine; design; diagnostic tool; differential expression; disability; economic cost; imaging approach; improved; in vivo; kinase inhibitor; macrophage; mouse model; multiple sclerosis patient; nanomolar; nervous system disorder; next generation; non-invasive imaging; novel; patient stratification; radiochemical; radioligand; radiotracer; repaired; response; response to injury; selective expression; success; tool; treatment response; treatment strategy; uptake; young adult

Project summary Multiple sclerosis (MS) is the most common disabling neurodegenerative condition that affects young adults around the world. Despite enormous efforts for treatment discovery, progressive disability, accompanied by very significant adverse personal, medical and economic costs, remains very common. An important reason that contributes to the unenviable track record of clinical trial failure for progressive MS is our inability to monitor in a precise manner the status of MS at any given time. Although it has been established that the inflammatory cells within the brain, known as microglia, are active in the progressive phase of the disease and most likely dictate outcome, we remain unable to differentiate between MS-mediator and reparative microglia. Therefore, there is a dire need to develop techniques that identify the subsets of microglia in order to stratify patients and offer them adequate treatment. Positron emission tomography (PET) has recently gained huge success as a non-invasive imaging approach to accurately quantify biological processes within the brain. Thus far, PET imaging in MS patients has been restricted to imaging a radioactive molecule, i.e. radioligand, that binds to a protein known as TSPO. However, the recently observed variation of the TSPO gene, with some patients lacking binding of the radioligands, and its inability to distinguish the activity of microglia limits its utility as a clinical and research tool. Building on our previous results showing the selective upregulated expression of a protein by reparative microglia, we will develop radioligands that bind to this protein and can be used for diagnostic purposes via PET. This highly translational research plan will enable clinicians to classify MS in novel ways to guide therapeutic intervention in MS patients in ways not previously possible. The specific aims of this project are to (i) design and synthesize next-generation radioligands with optimized binding and CNS penetration; (ii) generate radioactive versions of leading compounds; (iii) validate the radioligands in MS mouse brain slices and assess them by PET in MS mouse models. Outcome: This work will result in a diagnostic reagent that, using imaging equipment, will help clinicians monitor the status of progressive MS in patients being treated in a manner that has never been possible before and improve the success rates of new MS drugs being tested in clinical trials.

项目总结